Identification

Levamlodipine, also known as S-amlodipine, is a pharmacologically active enantiomer of amlodipine, an antihypertensive and anti-anginal medication. Levamlodipine belongs to the dihydropyridine group of calcium channel blockers. This medication is currently marketed in Russia and India 5. The names S-amlodipine and levamlodipine may be used interchangeably as both substances are the same, however, with differing nomenclature. As a racemic mixture, amlodipine contains (R) and (S)-amlodipine isomers, but only (S)-amlodipine as the active moiety possesses therapeutic activity 4.

Pharmacology

Levamlodipine decreases blood pressure and reduces cardiovascular oxygen demand, decreasing cardiovascular work. A study was done comparing the effectiveness of amlodipine and levamlodipine, and it was determined that 2.5 mg of S-amlodipine (levamlodipine) administered orally was equally effective as 5mg of amlodipine 4.

Mechanism of action

Levamlodipine blocks the transmembrane influx of calcium into the vascular and cardiac smooth muscles resulting in vasodilation and a subsequent decrease in blood pressure. This drug is an allosteric modulator and acts on the L-type calcium channels. It exerts the same mechanism of action, differing only in its form as an enantiomer 6.

The exact mechanisms by which levamlodipine relieves angina have not been fully understood, but the mechanism is thought to be twofold. Firstly, the modulation of calcium influx caused by levamlodipine leads to decreased peripheral resistance by arteriolar vasodilatation and subsequent reduction in oxygen requirement for cardiac muscle. Secondly, a decrease in coronary vascular resistance which can lead to an increase in coronary blood flow.

Negative inotropic effects can be demonstrated in vitro but such effects have not been observed in live animals at therapeutic doses 6.

Receptor binding studies of amlodipine have shown that out of the two enantiomer forms, only the (S) enantiomer of amlodipine (levamlodipine) binds to and blocks L-type calcium channels. The (R) enantiomer has no activity on these channels 5.

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

After oral administration of therapeutic doses, absorption produces peak plasma concentrations between 6 and 12 hours. Absolute bioavailability has been estimated to be between 64 and 90%. The bioavailability of amlodipine besylate tablets is not altered by the presence of food 6.

Extensively (about 90%) converted to its inactive metabolites by hepatic metabolism. Approximately 10% of the unchanged parent compound and 60% of its metabolites are excreted in the urine 8.

Studies suggest that CYP3A4, rather than CYP3A5, plays a key role in the metabolic clearance of amlodipine in humans 1.

In a metabolic study, or amlodipine enantiomers, S-amlodipine (levamlodipine) was slowly metabolized in human liver microsomes in vitro. Amlodipine dehydrogenation to the pyridine its metabolite, M9; the molecule underwent further underwent oxidative deamination, O-demethylation, and O-dealkylation. These in vitro metabolism data are consistent with amlodipine metabolism and disposition observed in vivo in humans. Data derived from amlodipine metabolism study in expressed P450 in human liver microsomes with P450 inhibitors indicate that CYP3A4 is the primary contributor to amlodipine dehydrogenation, rather than other liver enzymes such as CYP3A53.

Route of elimination

In one study, plasma concentration of (S)-amlodipine was measured after single dose oral administrations to 18 healthy volunteers. The concentration of (S)-enantiomer of amlodipine (Levamlodipine) was significantly higher than that of the inactive (R)-enantiomer (amlodipine). (S)-amlodipine was less rapidly eliminated than its (R) enantiomer 3.

If overdose should occur, vigilant cardiac and respiratory monitoring should be initiated. As with all calcium channel blockers, the risk of reflex tachycardia Frequent blood pressure measurements is required. Should hypotension occur, supportive measures including elevation of the extremities and administration of fluids should be initiated. Administration of vasopressors (such as phenylephrine) may be considered with attention to monitoring urine output. Intravenous calcium gluconate may reverse the effects of calcium entry blockade. As amlodipine is highly protein bound, hemodialysis is unlikely to be beneficial 6.

Taxonomy

Description

This compound belongs to the class of organic compounds known as dihydropyridinecarboxylic acids and derivatives. These are compounds containing a dihydropyridine moiety bearing a carboxylic acid group.